The goal of this application is to develop Dr. John Fingert into an independent clinician-scientist. Drs. Edwin Stone and Wallace Alward will assume responsibility as mentors to ensure success in his development in the fields of genetic research and ophthalmology. The core of this proposal is intensive training in genetic approaches to studying inherited forms of glaucoma. Glaucoma associated with pigment dispersion syndrome (PDS) is of particular interest for research due to its unique clinical features. PDS is common (affecting up to 2.5% of Americans) and due to the early age of onset, its effects on individuals and society may be felt for decades more than many other eye diseases. The defining characteristic of PDS is the release of pigment from the iris that causes many patients to develop pigmentary glaucoma and vision loss. Although structural and anatomical factors clearly contribute to the development of PDS, epidemiological and animal studies have provided strong evidence for a significant genetic component to the pathophysiology of this condition. The genetic basis of PDS is unknown, however, the University of Iowa has unique resources to facilitate the discovery of PDS-causing genes including a world class ophthalmic genetics research laboratory and a large collection of clinically-characterized PDS patients and pedigrees. The principle hypothesis of this proposal is that PDS may be caused by defects in genes involved in iris pigment production. To test this hypothesis we will search for PDS disease genes with three approaches: First, we will use positional cloning to identify the disease-causing gene in a large PDS pedigree. Second, we will genotype large cohorts of PDS patients and controls with genetic markers in search of an association between alleles of these markers and PDS. Third, we will screen our cohorts of PDS patients and controls for disease-causing mutations in genes associated with pigment production. These diverse approaches will facilitate the discovery of PDS-causing genes and provide insight into the pathogenesis of this disease, with the ultimate goal of facilitating improvements in the diagnosis and treatment of this condition. "Glaucoma is a common, blinding condition with genetic risk factors. One form of disease (pigmentary glaucoma) is caused by release of iris pigment within the eye. We are studying genes involved in pigment production as a cause of this form of glaucoma."